The NSAID sulindac reverses rectal adenomas in colectomized patients with familial adenomatous polyposis: clinical results of a dose-finding study on rectal sulindac administration

Winde, Günther; Gumbinger, H. G.; Oßwald, H.; Kemper, F. H.; Bünte, H

doi:10.1007/bf00341270

Cited by 93 publications

(32 citation statements)

References 26 publications

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“…This suggests that multiple apoptotic controls exist to control neoplasia in long-lived organisms such as the human. In colorectal mucosa, the first apoptotic control point appears to be mediated by APC, while a reserve system, (38)(39)(40)(41)(42). Because colorectal tumor cells lack intact APC, it was suggested that these NSAIDs replace a physiologic function of APC that was abrogated by mutation.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and APC in colorectal tumorigenesis.

Morin

Vogelstein²,

Kinzler³

1996

Proc. Natl. Acad. Sci. U.S.A.

433

326

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Tumors result from disruptions in the homeostatic mechanisms that regulate cell birth and cell death. In colon cancer, one of the earliest manifestation of this imbalance is the formation of polyps, caused by somatic and inherited mutations of the adenomatous polyposis coli (APC) tumor suppressor gene in both humans and mice. While the importance of APC in tumorigenesis is well documented, how it functions to prevent tumors remains a mystery. Using a novel inducible expression system, we show that expression of APC in human colorectal cancer cells containing endogenous inactive APC alleles results in a substantial diminution of cell growth. Further evaluation demonstrated that this was due to the induction of cell death through apoptosis. These results suggest that apoptosis plays a role not only in advanced tumors but also at the very earliest stages of neoplasia.

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Section: Discussionmentioning

confidence: 99%

Apoptosis and APC in colorectal tumorigenesis.

Morin

Vogelstein²,

Kinzler³

1996

Proc. Natl. Acad. Sci. U.S.A.

433

326

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“…However, the mode of action responsible for these effects is poorly understood. NSAIDs are potent inhibitors of Cox, the enzyme responsible for the formation of prostaglandins from arachidonic acid, and are used to treat familial adenomatous polyposis, a genetic disorder resulting in abnormal colorectal polyp formation, in humans (12). Until recently, the mode of action of NSAID was thought to be solely through inhibition of Cox, which, along with its products such as prostaglandin E 2 , is up-regulated in tumors and enhances the invasion of cancer cells via matrix metalloproteinase-2 (MMP-2; ref.…”

Section: Introductionmentioning

confidence: 99%

The anti-invasive activity of cyclooxygenase inhibitors is regulated by the transcription factor ATF3 (activating transcription factor 3)

Bottone

Moon

Kim

et al. 2005

Molecular Cancer Therapeutics

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We previously showed that nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide, which has chemopreventive activity, modulate the expression of several genes detected by microarray analysis. Activating transcription factor 3 (ATF3) was selected for further study because it is a transcription factor involved in cell proliferation, apoptosis, and invasion, and its expression is repressed in human colorectal tumors as compared with normal adjacent tissue. In this report, we show that ATF3 mRNA and protein expression are up-regulated in HCT-116 human colorectal cancer cells following treatment with NSAIDs, troglitazone, diallyl disulfide, and resveratrol. To ascertain the biological significance of ATF3, we overexpressed full-length ATF3 protein in the sense and antisense orientations. Overexpression of ATF3 in the sense orientation decreased focus formation in vitro and reduced the size of mouse tumor xenografts by 54% in vivo. Conversely, overexpression of antisense ATF3 was protumorigenic in vitro, however, not in vivo. ATF3 in the sense orientation did not modulate apoptosis, indicating another mechanism is involved. With microarray analysis, several genes relating to invasion and metastasis were identified by ATF3 overexpression and were confirmed by real-time reverse transcription-PCR, and several of these genes were modulated by sulindac sulfide, which inhibited invasion in these cells. Furthermore, overexpression of ATF3 inhibited invasion to a similar degree as sulindac sulfide treatment, whereas antisense ATF3 increased invasion. In conclusion, ATF3 represents a novel mechanism in which NSAIDs exert their anti-invasive activity, thereby linking ATF3 and its gene regulatory activity to the biological activity of these compounds. [Mol Cancer Ther 2005;4(5):693 -703]

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“…Sulindac sulfide inhibits the growth of tumor cells in soft agar (13,14), inhibits the growth of tumors in xenograft mouse models (14,15), and is a effective stimulator of apoptosis under a number of experimental conditions (8, 16 -22). In addition, sulindac and, hence, its metabolite, sulindac sulfide, are currently used to suppress the development of adenomatous polyps in patients with familial adenomatous polyposis (23). However, understanding the mechanisms responsible for the anti-tumorigenic activity of sulindac sulfide and other NSAIDs is lacking.…”

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confidence: 99%

Gene Modulation by the Cyclooxygenase Inhibitor, Sulindac Sulfide, in Human Colorectal Carcinoma Cells

Bottone

Martinez

Collins

et al. 2003

Journal of Biological Chemistry

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The mechanisms underlying the anti-tumorigenic properties of cyclooxygenase inhibitors are not well understood. One novel hypothesis is alterations in gene expression. To test this hypothesis sulindac sulfide, which is used to treat familial adenomatous polyposis, was selected to detect gene modulation in human colorectal cells at physiological concentrations with microarray analysis. At micromolar concentrations, sulindac sulfide stimulated apoptosis and inhibited the growth of colorectal cancer cells on soft agar. Sulindac sulfide (10 M) altered the expression of 65 genes in SW-480 colorectal cancer cells, which express cyclooxygenase-1 but little cyclooxygenase-2. A more detailed study of 11 genes revealed that their expression was altered in a time-and dose-dependent manner as measured by real-time RT-PCR. Northern analysis confirmed the expression of 9 of these genes, and Western analysis supported the conclusion that sulindac sulfide altered the expression of these proteins. Cyclooxygenase-deficient HCT-116 cells were more responsive to sulindac sulfide-induced gene expression than SW-480 cells. However, this response was diminished in HCT-116 cells overexpressing cyclooxygenase-1 compared with normal HCT-116 cells suggesting the presence of cyclooxygenase attenuates this response. However, prostaglandin E 2 , the main product of cyclooxygenase, only suppressed the sulindac sulfide-induced expression of two genes, with little known biological function while it modulated the expression of two more. The most likely explanation for this finding is the metabolism of sulindac sulfide to inactive metabolites by the peroxidase activity of cyclooxygenase. In conclusion, this is the first report showing sulindac sulfide, independent of cyclooxygenase, altered the expression of several genes possibly linked to its anti-tumorigenic and pro-apoptotic activity.

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The NSAID sulindac reverses rectal adenomas in colectomized patients with familial adenomatous polyposis: clinical results of a dose-finding study on rectal sulindac administration

Cited by 93 publications

References 26 publications

Apoptosis and APC in colorectal tumorigenesis.

Apoptosis and APC in colorectal tumorigenesis.

The anti-invasive activity of cyclooxygenase inhibitors is regulated by the transcription factor ATF3 (activating transcription factor 3)

Gene Modulation by the Cyclooxygenase Inhibitor, Sulindac Sulfide, in Human Colorectal Carcinoma Cells

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